One of the main limiting factors for effective prostate cancer drugs is toxicity - where normal cells and tissues are damaged by the drugs as well as cancerous cells and tissues, and Dr. Benyi Li of the University of Kansas, Medical Center Research Institute is using support from his FY08 Idea Development Award to address this problem in men with advanced prostate cancer.

Over the past several years, numerous approaches have been under development to target anticancer drugs specifically to only cancer cells so that the drugs can be used at their maximally effective doses. One such approach is the use of nanoparticles, which can carry drugs and release them for activity only upon nanoparticle contact with cancer cells. Dr. Li, a prostate cancer physician-scientist, in collaboration with Dr. Laird Forrest, a pharmaceutical chemist expert in nano-scale delivery of therapeutics, has been working to develop such agents for targeted therapy of prostate cancer and specifically targeting castration-resistant prostate cancer. This advanced form of prostate cancer, which typically progresses to lethality, arises in some men after hormone therapy that is given to limit the growth and progression of the disease. For these patients, treatment beyond hormone therapy is necessary, and so Drs. Li and Forrest's groups created a nanoparticle that targets a protein called PSMA, which is increasingly expressed on prostate cancer cells as they progress to more advanced stages. This nanoparticle could therefore deliver drugs specifically to advanced prostate cancer, sparing normal cells and tissues. Since Dr. Li's previous work had showed that the protein PI3K-p110beta plays a critical role in prostate cancer development and progression, he chose to load their PSMA-targeted nanoparticle with the pro-drug BL05, which is derived from TGX-221, a small chemical that specifically inhibits PI3K-p110beta activity and thus would be predicted to block tumor growth. The BL05-loaded nanoparticle was tested in a mouse model, where it completely abolished the growth of both hormone-sensitive and hormone-resistant tumors, indicating significant promise for further development of the agent. Dr. Li plans to continue developing the BL05-loaded nanoparticle, as well as other nanoparticle-driven approaches to targeted therapy (such as specifically delivering small interfering RNA against the androgen receptor in prostate cancer cells, also supported by the DoD PCRP), with the goal of eventually conducting clinical trials that would bring new and less toxic options for therapy to patients with advanced prostate cancer.